Compositions, kits, and methods for the diagnosis, prognosis, monitoring, treatment and modulation of post-transplant lymphoproliferative disorders and hypoxia associated angiogenesis disorders using galectin-1

Abstract

The present invention is based, in part, on the discovery that galectin-1 (Gal1) plays a role in viral-associated PTLD, e.g., EBV-associated PTLD and hypoxia associated angiogenesis disorders. Accordingly, the invention relates to compositions, kits, and methods for diagnosing, prognosing, monitoring, treating and modulating viral-associated PTLD, e.g., EBV-associated PTLD and hypoxia associated angiogenesis disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is the U.S. National Stage Application of International Application No. PCT / US2010 / 056547, filed on Nov. 12, 2010, which claims the benefit of priority to U.S. Provisional Application No. 61 / 335,779, filed on Jan. 12, 2010, U.S. Provisional Application No. 61 / 283,159, filed on Nov. 30, 2009, and U.S. Provisional Application No. 61 / 261,125, filed on Nov. 13, 2009; the entire contents of each of which application are expressly incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal conditions associated with immunocompromised solid organ and stem cell transplantation that can have 70-80% mortality (Gottschalk et al. (2005) Annu. Rev. Med. 56, 29-44; Paya et al. (1999) Transplantation 68, 1517-1525). PTLD is often associated with viral infection, such that latent viral infection of the transplanted material can cause complications in the tra...

AI Technical Summary

Benefits of technology

[0008]The present inventors have determined a vascular regulatory circuit involving Galectin-1 (Gal1), a member of a highly-conserved family of animal lectins, is expressed and secreted by a variety of tumors where it contributes to malignant transformation and metastasis (Paez-Ribes et al. (2009) Cancer Cell 15, 220-231; Liu et al. (2005) Nature Rev Cancer 5, 29-41), based on the differential glycosylation of ECs that promotes the formation of lectin-glycan lattices. These interactions couple tumor hypoxia to VEGFR2-mediated neovascularization through mechanisms that are independent of HIF-1α and VEGF. The ‘glycosylation signature’ of ECs can be selectively altered by tolerogenic, inflammatory, proliferative and hypoxic stimuli, which can either enable or hinder formation of these lattices. Targeted disruption of Gal1-glycan interactions, through Gal1 blockade or prevention of N-glycan branching, attenuated hypoxia-driven angiogenesis, while promoting extensive remodeling of vascular networks and increased influx and expansion of immune effector cells into the tumor parenchyma. These results underscore novel opportunities for targeting aberrant vascular networks, while simultaneously potentiating T cell-mediated antitumor immunity.

Problems solved by technology

PTLD is often associated with viral infection, such that latent viral infection of the transplanted material can cause complications in the transplant subject.

There is no accepted standard of therapy for PTLD, and the progression of the disease in patients is often not responsive to currently available therapies.

Management of early PTLD lesions is currently based on reduction or withdrawal of immunosuppression which increases the risk of graft rejection.

Yet, whether differential glycosylation enables the formation of discrete lectin-glycan lattices and signaling clusters that are functionally relevant to angiogenesis remains largely unexplored.

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